Iron deficiency is the most common micronutrient deficiency in the world, affecting 1.3 billion people (i.e., 24% of the world's population). Severe iron deficiency, i.e., iron deficiency anemia, is particularly debilitating, since iron has several vital physiological functions, including: (1) carrier of oxygen from lung to tissues; (2) transport of electrons within cells; and (3) co-factor of essential enzymatic reactions in neurotransmission, synthesis of steroid hormones, synthesis of bile salts, and detoxification processes in the liver. Among the consequences of iron deficiency anemia are increased maternal and fetal mortality, an increased risk of premature delivery and low birth weight, learning disabilities and delayed psychomotor development, reduced work capacity, impaired immunity (high risk of infection), an inability to maintain body temperature, and an associated risk of lead poisoning because of pica.
Iron deficiency anemia commonly affects patients having chronic diseases, such as kidney disease, inflammatory bowel disease, cancer, HIV, and diabetes. For example, patients receiving regular dialysis treatments for chronic renal failure very frequently are also afflicted with anemia. It is believed that prior to the availability of recombinant erythropoietin, a recombinant DNA version of the human erythropoietin protein that simulates the production of red blood cells, as many as about 90 percent of all kidney dialysis patients experienced debilitating anemia. A primary cause of anemia in dialysis patients is the inability of the kidneys to produce sufficient erythropoietin to generate adequate amounts of red blood cells. Although erythropoietin therapy simulates red blood cell production and is very often effective at reducing or eliminating anemia, iron deficiencies are also common among dialysis patients and can result in anemia despite erythropoietin therapy. Accordingly, in addition to erythropoietin therapy, it will often be necessary and desirable to deliver iron in a biologically available form to the blood of anemic dialysis patients in order to effectively treat the anemia. Further, there is evidence that iron supplementation can reduce the dose of erythropoietin needed to effectively treat anemia, even for patients that do not have an iron deficiency. This can be very important because recombinant erythropoietin is an expensive drug and can cause mild hypertension and flu-like symptoms. Therefore, it is often desirable to augment erythropoietin therapy with effective iron supplementation.
It is well known to treat an iron deficiency with orally administered iron supplements. Conventional oral iron fortificants can be divided into 4 groups: (1) freely water soluble (e.g., ferrous sulphate, ferrous gluconate, ferrous lactate and ferric ammonium citrate); (2) poorly water soluble (e.g., ferrous fumarate, ferrous succinate, and ferrous saccharate); (3) water insoluble (e.g., ferric pyrophosphate, ferric orthophosphate, and elemental iron); and (4) experimental [e.g., sodium-iron EDTA and iron-porphyrin (heme) complexes isolated from bovine hemoglobin].
In general, relatively large doses of oral iron fortificants are needed to achieve a desired therapeutic effect. The absorption of non-heme iron from the gastrointestinal tract varies from 2% to greater than 90% because it is strongly influenced by the iron status of the body, the solubility of the iron salts, the integrity of gut mucosa, and the presence of absorption inhibitors or facilitators in ingesta. For example, foods which contain polyphenol compounds and/or phytic acid bind with dietary iron, decreasing the concentration of free iron in the gut and forming complexes that are not absorbed. Cereals such as wheat, rice, maize, barley, sorghum and oats; vegetables such as spinach and spices; legumes such as soya beans, black beans, and peas; and beverages such as tea, coffee, cocoa and wine contain substances that inhibit iron absorption from the gut. L-Ascorbate and L-cysteine are known to facilitate absorption of iron.
Oral administration of iron supplements is known to be commonly accompanied by undesirable side effects, including nausea, vomiting, constipation and gastric irritation. For these and other reasons, patient noncompliance is also a common problem.
To overcome the above-described problems with oral delivery of iron, a great deal of effort has been directed to developing iron-containing formulations that are suitable for parenteral administration. Parenterally administered formulations are, in general, aqueous solutions of specific formulation components, in which the solution pH is in the range from about pH 4 to about pH 8. Parenteral administration encompasses administration by intravenous injection, intramuscular injection, or dialysis.
The formulation of iron-containing compositions for parenteral administration is particularly difficult. The solubility of iron compounds in water is strongly dependent on the pH of the solution and the presence of other formulation components. In general, iron salts are soluble in acidic solutions. Conversely, in basic solutions, unless a chelating agent, such as EDTA, is present, iron ions will form insoluble oxides and precipitate from the formulation.
In addition, formulation of iron compounds in aqueous solutions presents added degrees of difficulty related to the redox chemistries of iron and its ability to catalyze oxidation reactions. With respect to redox chemistries, iron has two common oxidation states, the ferrous or Fe+2 state and the ferric or Fe+3 state. In general, iron compounds in which iron is in its ferrous oxidation state are more soluble in water than are iron compounds in which iron is in its ferric oxidation state. In the presence of reducing agents, such as L-ascorbate or L-cysteine, iron is known to cycle from its ferric to its ferrous oxidation state and vice versa. Iron ions in solution are highly reactive oxidizing agents and catalysts for oxidation of other formulation components. For example, iron ions in solution are known to catalyze oxidation of dextrose, polysaccharides, amines, and phenols to cause formation of degradation products having undesirable properties, such as color, biological activities, and toxicities that are different from those of the unoxidized substances.
With respect to intravenous administration, iron dextran (INFED®), which may be obtained from Watson Pharmaceuticals, Corona, Calif., is formulated in water containing 0.9% (by weight) sodium chloride for parenteral administration. [Physicians Desk Reference, 59th edition, 2005, pages 3301-3303]. Iron dextran is a dextran macromolecule having a molecular weight ranging generally between about 100,000 and about 200,000 to which iron is bound by both ionic bonds and weak electrostatic interactions. Iron dextran thus formulated occasionally causes severe allergic reactions, fever and rashes during injection. Parenteral administration intramuscularly is painful and often results in an undesirable discoloration at the injection site. Further, only about half of the iron in iron-dextran is bioavailable after intravenous injection. The fate of the rest is unknown.
Intravenous administration of iron saccharide complexes such as iron dextran requires venous access and the commercially available intravenously administered iron supplements, such as iron dextran and ferric gluconate, are relatively expensive and require a great deal of time and skill to administer.
Intraperitoneal delivery of iron dextran has been used to treat anemia. However, there is evidence that iron dextran, when administered intraperitoneally, is stored in macrophages near the peritoneum and could create abnormal changes in the peritoneum.
Other iron preparations which may be administered by injection are taught in U.S. Pat. No. 5,177,068 to Callingham et al., U.S. Pat. No. 5,063,205 to Peters and Raja, U.S. Pat. No. 4,834,983 to Hider et al., U.S. Pat. No. 4,167,564 to Jenson, U.S. Pat. No. 4,058,621 to Hill, U.S. Pat. No. 3,886,267 to Dahlberg et al., U.S. Pat. No. 3,686,397 to Muller, U.S. Pat. No. 3,367,834 to Dexter and Rubin, and U.S. Pat. No. 3,275,514 to Saltman et al., for example. In general, these are formulations of iron bound to polymeric substrates, or chelated by various ligands, saccharides, dextrans, hydrolyzed protein, etc. All have been unsuccessful and/or possess such severe adverse side effects that practical utilization has not occurred.
It is known to deliver iron to an iron-deficient patient via dialysis using a composition comprising an ionic iron complex. An advantage is that the dialysis treatment delivers iron to the blood at a relatively constant rate throughout the dialysis session. This is because there is negligible free iron in plasma since iron rapidly binds with transferrin.
Soluble ferric pyrophosphate (alternatively, “ferric pyrophosphate, soluble”) is an iron preparation of uncertain composition. No definite formula for its constitution is known. In general, it is described as “a mixture of ferric pyrophosphate and sodium citrate” or “a mixture of four salts (ferric and sodium pyrophosphates and ferric and sodium citrates)” or “ferric pyrophosphate that has been rendered soluble by sodium citrate.” Soluble ferric pyrophosphate is known to have the properties described in Table 1.
TABLE 1Properties of Conventional Ferric Pyrophosphate, SolubleParameterObservationChemical Name1,2,3-Propanetricarboxylic acid, 2-hydroxy-,iron(3+) sodium salt (1:1:1), mixture with iron(3+)diphosphateCAS Registry No.1332-96-3AppearanceSolid (may be plates, powder, or pearls, dependingon the manufacturer)ColorYellow-green to apple-greenIron content10.5% to 12.5%Solubility in waterExceeds 1 g per mLpH of a 5% solution5-7
Soluble ferric pyrophosphate may be obtained commercially. Conventional soluble ferric pyrophosphate is an apple-green solid containing from about 10.5% to about 12.5% iron. According to the manufacturers, soluble ferric pyrophosphate is stable for as long as three years provided that it is protected against exposure to air and light. Analysis of conventional soluble ferric pyrophosphates has shown that typical conventional preparations contain iron, pyrophosphate anion, citrate anion, phosphate anion, sulfate anion, and sodium (Table 2).
TABLE 2Composition of conventional soluble ferric pyrophosphatesWeight Percent Composition on the Dried BasisSample No.ABCDEFIron11.811.411.911.112.012.0Pyrophosphate10.18.34.79.19.210.1Citrate34.335.944.237.635.836.5Phosphate16.817.112.915.817.416.3Sodium16.016.116.616.216.416.2Sulfate12.616.415.919.514.64.2
Methods for the preparation of the mixture known as soluble ferric pyrophosphate are provided by Caspari. (Charles Caspari, “Treatise on Pharmacy for Students & Pharmacists, Lea Brothers & Co., 1906, pages 556-557.) A preparation disclosed by Caspari is made by precipitating a white ferric pyrophosphate, Fe4(P2O7)3, from a solution of ferric sulphate by means of sodium pyrophosphate, dissolving this precipitate in a solution of sodium or ammonium citrate and concentrating and scaling the solution so obtained. In the alternative, Caspari wrote that this iron preparation is made by adding 11 parts of crystallized sodium pyrophosphate to a solution of 11 parts of ferric citrate in twice its weight of water, evaporating the resulting green-colored solution at a temperature not exceeding 60° C. (140° F.) to obtain a syrupy consistency, and spreading the syrupy material on glass plates to allow solidification. Although modern processing techniques have likely been applied to the latter method of preparation, the process suffers from a number of serious drawbacks, including the fact that ferric citrate, a key starting material, is an unstable substance of unknown composition; the consistency and viscosity of a “syrupy” composition is undefined; and the means for isolating and purifying the product are not disclosed. Irrespective of the conventional method of preparation, examination of Table 2 clearly shows that the anion composition of conventional soluble ferric pyrophosphate is widely variable, with a pyrophosphate content ranging from about 4.7% to about 10.1%; a citrate content ranging from about 34.3% to about 44.2%; a phosphate content ranging from about 12.9% to about 17.4%; and a sulfate content ranging from about 4.2% to about 19.5%.